WO2004098634A2 - Proteine arginine n-methyltransferase 2 (prmt-2) - Google Patents

Proteine arginine n-methyltransferase 2 (prmt-2) Download PDF

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WO2004098634A2
WO2004098634A2 PCT/US2004/013375 US2004013375W WO2004098634A2 WO 2004098634 A2 WO2004098634 A2 WO 2004098634A2 US 2004013375 W US2004013375 W US 2004013375W WO 2004098634 A2 WO2004098634 A2 WO 2004098634A2
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prmt
cell
activity
cells
expression
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WO2004098634A3 (fr
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Elizabeth G. Nabel
Gary J. Nabel
Takanobu Yoshimoto
Hiroaki Iwasaki
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Government Of The United States Of America As Represented By The Sercretary Of The Department Of Health And Human Services National Institutes Of Health
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Publication of WO2004098634A2 publication Critical patent/WO2004098634A2/fr
Publication of WO2004098634A3 publication Critical patent/WO2004098634A3/fr
Priority to US11/263,657 priority Critical patent/US20060239990A1/en

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Definitions

  • Inhibition is sequence-specific in that nucleotide sequences corresponding to the duplex region of the RNA are targeted for genetic inhibition.
  • siRNA containing nucleotide sequences identical to a portion of the target gene is preferred for inhibition.
  • siRNA sequences with insertions, deletions, and single point mutations relative to the target sequence have also been found to be effective for inhibition.
  • sequence identity may optimized by alignment algorithms known in the art and calculating the percent difference between the nucleotide sequences.
  • the duplex region of the RNA may be defined functionally as a nucleotide sequence that is capable of hybridizing with a portion of the target gene transcript.
  • Anti-sense nucleic acids can also be used to inhibit the function of PRMT-2.
  • the function of PRMT-2 RNA is inhibited, for example, by administering to a mammal a nucleic acid that can inhibit the functioning of PRMT-2 RNA.
  • Nucleic acids that can inhibit the function of a PRMT-2RNA can be generated from coding and non-coding regions of the PRMT-2 gene.
  • the degree of complementarity or sequence identity of hybrids obtained during hybridization is typically a function of post-hybridization washes, the critical factors being the ionic strength and temperature of the final wash solution.
  • the type and length of hybridizing nucleic acids also affects whether hybridization will occur and whether any hybrids formed will be stable under a given set of hybridization and wash conditions.
  • An example of stringent hybridization conditions for hybridization of complementary nucleic acids that have more than 100 complementary residues on a filter in a Southern or Northern blot is 50% formamide with 1 mg of heparin at 42 °C, with the hybridization being carried out overnight.
  • An example of highly stringent conditions is 0.1 5 M NaCl at 72 °C for about 15 minutes.
  • Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (NH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • NH variable domain
  • VL variable domain at one end
  • Antibody fragments retain some ability to selectively bind with its antigen or receptor and are defined as follows:
  • the monoclonal antibodies for use with the present invention may also be isolated from antibody libraries using the techniques described in Clackson et al. Nature 352: 624-628 (1991), as well as in Marks et al, J. Mol Biol. 222: 581-597 (1991).
  • adenovirus gene delivery vehicles can also be readily prepared and utilized given the disclosure provided herein (see also Berkner, Biotechniques 6:616-627, 1988, and Rosenfeld et al., Science 252:431-434, 1991, WO 93/07283, WO 93/06223, and WO 93/07282).
  • naked nucleic acid molecules are used as gene delivery vehicles, as described in WO 90/11092 and U.S. Pat. No. 5,580,859.
  • the therapeutic agents of the invention are prepared for oral administration, they are generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form.
  • the therapeutic agents may be present as a powder, a granular formulation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of the active ingredients from a chewing gum.
  • the therapeutic agents may also be presented as a bolus, electuary or paste.
  • Orally administered therapeutic agents of the invention can also be formulated for sustained release, e.g., the therapeutic agents can be coated, micro-encapsulated, or otherwise placed within a sustained delivery device.
  • the total active ingredients in such formulations comprise from 0.1 to 99.9% by weight of the formulation.
  • polypeptides or antibodies are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the therapeutic agents, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time.
  • Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g., stents, catheters, peritoneal dialysis tubing, draining devices and the like.
  • Polypeptides, nucleic acids or antibodies of the present invention may be formulated as dusting powders and comprise finely divided particles having an average particle size of between about 1 and 5 ⁇ m, alternatively between 2 and 3 ⁇ m.
  • Finely divided particles may be prepared by pulverization and screen filtration using techniques well known in the art.
  • the particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular infection, indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • PRMT-2- A represents an alternatively spliced form of PRMT-2 found in the expressed sequence tag (EST) database. This isoform contains the first 218 amino acids of PRMT-2 and differs from full
  • PRMT-2 The potential methyltransferase activity of PRMT-2 was examined by an immune complex methylation assay following PRMT-2 transfection.
  • PRMTl the predominant PRMT in mammalian cells, was used as a positive control for methylation activity.
  • Expression vectors containing HA-tagged PRMTl or PRMT-2 were transfected into 293 cells.
  • histone H2A was highly methylated in PRMTl immune precipitates. Chen et al. (1999) Science, 284, 2174-7.
  • FIG. 6C (lanel) confirms these observations.
  • PRMT-2 weakly methylated histone H2A when immunoprecipitated from transfected cells ( Figure 6C, lane 3).
  • Immunoprecipitates from the lysate of the empty vector transfection did not methylate histone H2A (FIG. 6C lane2).
  • the E2F transcription factor is one of the major targets of Rb. Dyson, N. (1998) Genes Dev, 12, 2245-62; Harbour and Dean (2000) Genes & Development, 14, 2393-2409.
  • PRMT-2 regulates the transcriptional activation by E2F
  • HeLa cells were transfected with a vector encoding the GAL4 luciferase reporter gene (G5E4T-Luc), and an expression vector encoding a GAL4 DNA binding domain that was fused to the E2F1 activation domain (pHKGAL4 E2F1-AD; FIG. 7A).
  • PRMT-2 plays diverse roles in transcriptional regulation through different mechanisms that depend on its binding partner.
  • the present study indicates that RB is indispensable for the E2F repression by PRMT-2, suggesting that PRMT-2 may recruit other co- repressors, or may affect the function of other co-repressor in RB complex.
  • Sections (5 ⁇ m thick) from Bousin's fixed paraffin-embedded specimens were stained with hematoxylin and eosin, and periodic acid Schiff (PAS), and examined by light microscopy.
  • Mouse fibroblasts were grown to 80% confluence on a 10 cm plate. Cells were washed and scraped off the plate into 500 ⁇ l of PBS (pH 7.4), and were lysed by sonication. After centrifugation at 15,000 ⁇ m for 10 min at 4 °C, the supernatants were used as the enzyme source.
  • Rb targets histone H3 methylation and HP1 to promoters. Nature, 412, 561-565. Robertson, K.D., Ait-Si-Ali, S., Yokochi, T., Wade, P.A., Jones, P.L. and Wolffe, A.P.

Abstract

La présente invention s'intéresse à la fonction de la protéine arginine N-méthyltransférase-2 (PRMT-2) et concerne des procédés permettant de moduler l'activité ou l'expression de la PRMT-2 dans des cellules. Les procédés de cette invention peuvent être utilisés pour inhiber la fonction de NFλB, E2F1 et STAT3 et sont utiles dans le traitement d'une variété d'états tels que l'inflammation, l'infection par le VIH, le cancer et l'obésité.
PCT/US2004/013375 2003-04-30 2004-04-30 Proteine arginine n-methyltransferase 2 (prmt-2) WO2004098634A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006069155A2 (fr) * 2004-12-21 2006-06-29 Bristol-Myers Squibb Company Inhibiteurs de methyl-transferases d'arginine de proteines
WO2007071069A1 (fr) * 2005-12-22 2007-06-28 Institut De Cardiologie De Montreal Oligonucleotides presentant plusieurs elements cis, servant de leurre a un facteur de transcription
CN100516232C (zh) * 2006-07-19 2009-07-22 中国科学院遗传与发育生物学研究所 蛋白质精氨酸甲基转移酶5在白血病细胞检测和治疗中的应用
WO2011034421A1 (fr) * 2009-09-16 2011-03-24 Stichting Het Nederlands Kanker Instituut Gènes cibles fra-1 utilisés comme cibles médicamenteuses pour le traitement du cancer

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WO2008144011A1 (fr) * 2007-05-16 2008-11-27 Avalon Pharmaceuticals Compositions et procédés pour traiter ou empêcher des maladies auto-immunes
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